This is a proposal to perform a genome-wide gene expression profiling in peripheral blood in a sample of Amyotrophic Lateral Sclerosis (ALS) patients and matched controls, all from a relatively homogeneous population in The Netherlands. Once ALS-specific expression profiles have been identified, these will be used as phenotypes to identify underlying genetic variation. A replication sample is available from the same population as well as samples with ALS-related phenotypes. Identification of ALS-specific expression profiles equals the discovery of functional biomarkers for the disease. Since variation in gene expression is to a large degree associated with genetic variation, these functional biomarkers can be used to identify common genetic variants associated with the complex neurological disorder of ALS. The study population is ideal for genetic studies given the uniformity of its ascertainment, the population-based sample collection, and the homogeneous population structure. The patients remain under care of the same clinicians who enrolled them in the study, permitting unusual opportunities for longitudinal evaluations within the time span of the disease, as well as family-based follow-up studies. Genome-wide expression profiles will be established for the sample using the high- throughput BeadChip arrays containing >23,000 RefSeq transcripts. Systematic statistical analyses will be applied in order to identify gene-expression profiles associated with ALS phenotype. Network-based analysis will be performed to identify expression modules, and the most significant changes related to disease phenotype(s). Since for the vast majority of these samples high-density 300K SNP genotyping is available through an independent effort, the expression profiles can be used as quantitative traits for genome-wide association studies. Follow-up studies will be initiated to further delineate the underlying genetic variation associated with ALS expression profiles as well as study of specific ALS characteristics and expression profiles. Ultimately, the developments of functional biomarkers for ALS can be used for diagnostic purposes and identification of underlying genetic variation associated with ALS-specific expression profiles and disease susceptibility. This is a proposal to perform a genome-wide gene expression profiling in peripheral blood in a sample of Amyotrophic Lateral Sclerosis (ALS) patients and matched controls, all from a relatively homogeneous population in The Netherlands.